ST6GALNAC1 plays important roles in enhancing cancer stem phenotypes of colorectal cancer via the Akt pathway
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Tadashi Ogawa1,2, Yoshihiko Hirohashi1, Aiko Murai1, Toshihiko Nishidate2, Kenji Okita2, Liming Wang1, Yuzuru Ikehara3, Tetsuta Satoyoshi1,2, Akihiro Usui1,2, Terufumi Kubo1, Munehide Nakastugawa1, Takayuki Kanaseki1, Tomohide Tsukahara1, Goro Kutomi2, Tomohisa Furuhata2, Koichi Hirata2, Noriyuki Sato1, Toru Mizuguchi2, Ichiro Takemasa2 and Toshihiko Torigoe1
1Department of Pathology, Sapporo Medical University School of Medicine, Chuo-Ku, Sapporo 060-8556, Japan
2Department of Surgery, Sapporo Medical University School of Medicine, Chuo-Ku, Sapporo 060-8556, Japan
3The Molecular Medicine Team, Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology, Tsukuba 305-8568, Japan
Yoshihiko Hirohashi, email: [email protected]
Toshihiko Torigoe, email: [email protected]
Keywords: colorectal cancer, cancer stem cell, ST6GALNAC1, STn antigen, Akt pathway
Received: June 16, 2017 Accepted: October 04, 2017 Published: November 08, 2017
Colorectal cancer (CRC) is a mortal disease due to treatment resistance, recurrence and distant metastasis. Emerging evidence has revealed that a small sub-population of cancer cells termed cancer stem cells (CSCs)/ cancer-initiating cells (CICs) is endowed with high levels of tumor-initiating ability, self-renewal ability and differentiation ability and is responsible for treatment resistance, recurrence and distant metastasis. Eradication of CSCs/CICs is essential to improve current treatments. However, the molecular mechanisms by which CSCs/CICs are maintained are still elusive. In this study, we aimed to determine the molecular mechanisms by which colorectal (CR)-CSCs/CICs in are maintained human primary CRC cells. CR-CSCs/CICs were isolated by sphere-culture and the ALDEFLUOR assay, and transcriptome analysis revealed that the gene ST6 N-Acetylgalactosaminide Alpha-2,6-Sialyltransferase 1 (ST6GALNAC1) was expressed at high levels in CR-CSCs/CICs. Overexpression of ST6GALNAC1 enhanced the expression of sialyl-Tn (STn) antigen, which is carried by the CSC marker CD44, and increased the sphere-forming ability and resistance to a chemotherapeutic reagent. The opposite phenomena were observed by gene knockdown using siRNA. Furthermore, the Akt pathway was activated in ST6GANAC1-overexpressed cells, and activation of the pathway was cancelled by gene knockdown of galectin-3. The results indicate that ST6GALNAC1 has a role in the maintenance of CR-CSCs/CICs by activating the Akt pathway in cooperation with galectin-3 and that ST6GalNAC1 (or STn antigen) might be a reasonable molecule for CSC/CIC-targeting therapy.
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